Investigating the role of NOL3 in normal hematopoiesis and myeloid malignancy

Abstract

Myeloid malignancies are a group of heterogeneous hematopoietic diseases that arise due to aberrations in a clonal population of hematopoietic stem and progenitor cells. Philadelphia chromosome negative (Ph-) myeloproliferative neoplasms (MPN) include essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF) and are united by the discovery of recurrent oncogenic driver mutations that lead to constitutive JAK-STAT activation. Of the P- MPNs, PMF has the most severe morbidity and greatest mortality. The pathogenesis of PMF is incompletely understood and the identification of novel mechanisms that contribute to disease initiation is critical for understanding the molecular pathways that drive these diseases. Apoptosis repressor with caspase recruitment domain (ARC) is encoded by the Nol3 gene and is highly expressed in heart, skeletal muscle, and brain. In these tissues, ARC is a potent inhibitor of cell death and can antagonize both the intrinsic and extrinsic apoptosis pathways. The role of ARC in normal and malignant hematopoiesis is largely unclear and has not yet been investigated using genetically engineered mouse models. In this study, we show that deletion of Nol3 (Nol3-/-) in mice leads to development of a MPN phenotype resembling PMF. The Nol3 -/-induced MPN is characterized by anemia, thrombocytopenia, extramedullary hematopoiesis, and bone marrow fibrosis. Transplantation of Nol3 -/- MPN bone marrow cells recapitulates the disease phenotype in recipient mice. Microarray profiling of an expanded Nol3-/- MPN Thy1+LSK cell population revealed significant enrichment of MYC target genes and genes involved in NFKB activation. Furthermore, these Thy1+LSK cells are actively cycling and display a myeloid differentiation bias ex vivo that is, at least in part, mediated by activation of CDK6 and Myc. Additionally, we show that NOL3 is deleted in a fraction of patients with myeloid malignancies and that restoration of ARC expression in HEL cells has anti-leukemic effects. In summary, our studies provide a novel PMF-like mouse model in which genetic.